Hedgehog Signaling as a regulator of progenitor differentiation for organ maintenance and disease

PROJECT SUMMARY The Hedgehog (Hh) singling pathway orchestrates organ development, but its precise timing remains unclear. This project investigates whether Hh acts as a "heterochronic switch," controlling differentiation timing across organs. We aim to decipher the heterochronic switch role of Hh singling in lung development and potential contribution to two major lung diseases (COPD and IPF). Using a robust computational pipeline, we will analyze existing single-cell data from mouse and human lungs with three specific aims: 1) Deciphering Hh's temporal control: We'll analyze existing mouse datasets to understand how altered Hh impacts differentiation in both loss-of- function and gain-of-function scenarios. 2) Unveiling human lung dynamics: We will classify, track, and characterize Hh-receiving cells across fetal and adult lungs, comparing them to reveal changes in Hh timing control during development. And 3) Connecting Hh to disease: We will assess the impact of altered Hh signaling on lineage-specific cell populations in COPD and IPF, identifying disease-specific Hh target genes for further investigation. This proposed computational work could assess whether and how Hh acts as a differentiation timing control on lung progenitors, in normal development and disease. The impacts of this project include: (1) the first quantification of Hh's role in regulating lung differentiation timing; (2) a set of disease- and lineage-specific Hh target genes, potentially leading to new therapeutic strategies, and (3) a validated pipeline for studying heterochronic control in other organs. Therefore, success of this project can enhance our understanding of organ regeneration and disease pathogenesis. Beyond lung diseases, this project could potentially illuminate Hh's heterochronic role in various organs and diseases, paving the way for novel diagnostic and therapeutic approaches.